Sepsis/Multiple Organ Dysfunction Syndrome and Early Goal Directed Therapy Michael J. Apostolakos, MD Associate Professor of Medicine Director of Adult Critical Care University of Rochester

Sepsis: Epidemiology ~ 750,000 cases per year ~200,000 deaths per year Increased incidence and mortality with age and co-morbidity 2/3 occur in hospitalized patients Incidence increasing in the North America Angus et.al., CCM 2001:291303-1310

Systemic Inflammatory Response Syndrome (SIRS) A complex systemic response which includes two or more of the following manifestations: fever or hypothermia (>38oc or < 36oc) tachycardia (> 90 beats/min) tachypnea (> 20 breaths/min) WBC count of > 12,000 or <4,000 cells/mm3 or > 10% immature neutrophils CCM 20:864-874, 1992

Sepsis Severe Sepsis Confirmed or suspected infection, plus > 2 SIRS criteria Sepsis > 1 organ dysfunction CCM 20:864-874, 1992

Septic Shock Sepsis with hypotension (SBP < 90 mm Hg or a reduction of > 40 mm Hg from baseline) despite adequate fluid resuscitation along with perfusion abnormalities: lactic acidosis oliguria altered mental status CCM 20:864-874, 1992

Sepsis: A Complex Disease This Venn diagram provides a conceptual framework to view the relationships between various components of sepsis. The inflammatory changes of sepsis are tightly linked to disturbed hemostasis. This conceptual framework shows the interrelationships between infection, non-infectious disorders, SIRS, sepsis, and severe sepsis. Components of the process not discussed on the following slides include: Infection: a microbial phenomenon characterized by an inflammatory response to the presence of microorganisms or the invasion of normally sterile host tissue by those organisms Bacteremia: the presence of viable bacteria in the blood stream Septic shock: sepsis-induced hypotension despite adequate fluid resuscitation along with the presence of perfusion abnormalities that may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status Multiple organ dysfunction syndrome (MODS): presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention Inflammation and hemostasis are tightly linked. Therefore, although not shown on this slide, sepsis and severe sepsis lie on a background of disturbed hemostasis. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest. 1992;101:1644-55. Opal SM, Thijs L, Cavaillon JM, et al. Relationships between coagulation and inflammatory processes. Crit Care Med. 2000;28:S81-2. Adapted from: Bone RC et al. Chest. 1992;101:1644-55. Opal SM et al. Crit Care Med. 2000;28:S81-2.

Sepsis: Etiology ~ 1/2 culture positive cases are gram negative organisms ~ 1/2 gram positive organisms 2 - 5% fungi or mixed infections Mycobacteria, rickettsiae, viruses and protozoans may cause sepsis 1/3 of cases culture negative

Sepsis: A Network of Cascading Events INFLAMMATION PROINFLAMMATORY MEDIATORS Activated Protein C T TM ANTI-INFLAMMATORY MEDIATORS PAI-1 T-PA TAF-1 INFECTION ENDOTHELIAL INJURY TF COAGULATION Severe sepsis is associated with three integrated components: Infection with the systemic activation of inflammation. During progression of sepsis, a wide variety of proinflammatory cytokines is released. Endotoxin induces rapid increases in the levels of tumor necrosis factor (TNF), interleukin-1 (IL-1), and interleukin-6 (IL-6) in experimental models of sepsis. These proinflammatory cytokines are linked to the development of the clinical signs of sepsis. Release of proinflammatory cytokines is associated with endothelial injury and vascular bed-specific changes in the thrombogenicity of the endothelium.These can include increased tissue factor (TF) expression in a subset of endothelial cells and release of plasminogen activator inhibitor-1 (PAI-1). Activation of coagulation. Inflammatory changes trigger the extrinsic pathway of coagulation. Activation of coagulation in patients with sepsis is not always disseminated intravascular coagulation. Instead, in most patients, it is a subclinical activation of the hemostatic system as indicated by changes in commonly measured hemostatic parameters. Experimentally, there are increases in thrombin-antithrombin (TAT) complexes. Clinical laboratory findings include significant increases in D-dimer, a marker of coagulation and associated fibrinolysis. Impairment of fibrinolysis. In patients with sepsis, plasminogen levels fall rapidly while antiplasmin levels remain normal. This decreases the normal fibrinolytic response. Fibrinolysis is further impaired by release of PAI-1 and the generation of increased amounts of thrombin-activatable fibrinolysis inhibitor (TAFI). Although plasminogen/antiplasmin ratio and PAI-1 levels remain abnormal in nonsurviving patients, they tend to normalize in survivors. Kidokoro A, Iba T, Fukunaga M, et al. Alterations in coagulation and fibrinolysis during sepsis. Shock. 1996;5:223-28. Levi M, van der Poll T, ten Cate H, et al. The cytokine-mediated imbalance between coagulant and anticoagulant mechanisms in sepsis and endotoxaemia. Eur J Clin Invest. 1997;27:3-9. Lorente JA, Garcia-Frade LJ, Landin L, et al. Time course of hemostatic abnormalities in sepsis and its relation to outcome. Chest. 1993;103:1536-42. van Deventer SJH, Buller HR, ten Cate JW, et al. Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood. 1990;76:2520-6. Vervloet MG, Thijs LG, Hack CE. Derangements of coagulation and fibrinolysis in critically ill patients with sepsis and septic shock. Semin Thromb Hemost. 1998;24:33-44. FIBRINOLYSIS Copyright © 2001, Eli Lilly and Company. All rights reserved.

Multiple Organ Dysfunction Syndrome Often caused by sepsis (also caused by trauma, pancreatitis, hypovolemia, etc.) Iatrogenic disorder that did not exist prior to 1950s (patients simply died) May be exacerbated by by mechanical ventilation, high glucose levels, pressors, fluids etc. Goal is to prevent! Remove trigger Maximize tissue perfusion Minimize iatrogenic injury

Sepsis: Current Treatment Removal of source of infection Antimicrobials Fluid resuscitation Hemodynamic support (new role for vasopressin?) General supportive care ? Attack inflammatory response

Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock Retrospective cohort design 2,731 adult patients with septic shock Administration of effective abx for isolated or suspected pathogen was associated with 80% survival Each hour delay associated with 8% reduction in survival Only 50% of septic shock patients received abx with 6 hours of hypotension Kumar et al, CCM 34:1589-1596, 2006

Inadequate Antimicrobial Treatment of Infections: A Risk factor for Hospital Mortality Among Critically Ill Patients Evaluated 2000 patients for the relationship between inadequate antimicrobial treatment and hospital mortality for patients requiring ICU admission 169 (8.5%) infected patients initially received inadequate antimicrobial treatment of infection Most commonly nosocomial infections treated inadequately 52% mortality in inadequately treated vs 12% in adequately treated Should treat nosocomial infections broadly and then narrow after 48 hours Kollef et al, CHEST 1999;115,462-474

Septic Shock: HemodynamicTherapy Adequate volume resuscitation (colloids vs crystalloid) ? Swan-Ganz Catheter ? SVO2 monitor Dopamine Norepinephrine Phenylephrine if tachyarrthymias Vasopressin in refractory hypotension

Negative Fluid Balance Predicts Survival in Patients with Septic Shock Retrospectively evaluated 36 patients with septic shock Extracted demographic and physiologic data Variables compared with survivors and non-survivors and those who reached negative fluid balance in the first 3 days (Greater than 500 ml over 24 hours) All 11 patients who reached negative fluid balance survived. Only 5/25 who didn’t survived Alsous et al CHEST 2000;117:1749-1754

“You have to swell to get well” Don Smith, MD circa 1994 Quotables “You have to swell to get well” Don Smith, MD circa 1994

Norepinephrine or Dopamine for the Treatment of Hyperdynamic Septic Shock? 32 patients with hyperdynamic septic shock randomized to receive dopamine (2.5-25 mcg/kg/min) or NE (0.5 - 5.0 mcg/min) Goal to achieve at 6 hours (1) SVR > 1,100 dynes and/or MAP > 80 mm Hg (2) CI > 4.0 L/min/m2 (3) DO2 > 550 ml/min/m2 (4) VO2 > 150 ml/min/m2 Dopamine 5/16 achieved goal, NE 15/16 reached goal 10/11 Dopamine patients who failed, met goal when NE started NE more reliable at reversing septic shock hemodynamics Martin et al, CHEST 1993;103:1826-31

Vasopressin Deficiency Contributes to the Vasodilation of Septic Shock 19 patients with vasodilatory septic shock Administered 0.04 U/min continuous infusion AVP BP increased from 92/52 to 146/66 (p<.001) SVR increased from 644 to 1187 dynes (p<.001) Mean vasopressin level 3.1 pg/mL vs 22.7 in patients with cardiogenic shock Vasopressin levels normalized with infusion Landry et al 1997;95:1122-1125

Mortality rates 35% vs 39% (non-significant) Vasopressin versus Norepinehrine Infusion in Patients with Septic Shock 778 patients on minimum of 5 mcg/min NE were randomized to receive low dose vasopressin (0.01 to 0.03 units/min) or NE 5-15 mcg/min Mortality rates 35% vs 39% (non-significant) NEJM 2008;358:877-887.

Oxygen Consumption/Delivery VO2 = CO x (CaO2 - CvO2) DO2 = CO x (CaO2) CaO2 = {O2 sat x Hg (gm/dL) x 1.34 ml O2/gm Hg} + PaO2 (0.003 ml O2/mm Hg)

A Trial of Goal-Oriented Hemodynamic Therapy in Critically Ill Patients Randomly assigned 756 critically ill patients to control, cardiac-index group and oxygen-saturation group Mortality rates were 48.4%, 48.6% and 52.1% respectively Number of organ dysfunctions and ICU length of stay were similar Gattinoni et al N Engl J Med 333:1025-1032, 1995

The Effectiveness of Right Heart Catheterization in the Initial Care of Critically Ill Patients Examined the association between the use of right heart catheterization (RHC) and subsequent survival, length of stay, intensity of care and cost of care Prospective-cohort study Five US teaching hospitals 5735 critically ill adult patients, each had a propensity score for receiving RHC Conners et al, JAMA 276:889-897, 1996

The Effectiveness of Right Heart Catheterization in the Initial Care of Critical Ill Patients: Results Patients with RHC had increased 30 day mortality (odds ratio 1.24) Mean cost per hospital stay $49,300 (RHC) vs $35,700 (no RHC) LOS in ICU 14.8 days (RHC) vs 13.0 days (no RHC) Connors et al, 276:889-897, 1996

Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock Assigned 263 patients with severe sepsis or septic shock to six hours of conventional or goal directed therapy Standard: CVP 8-12, MAP > 65, U/O > 0.5 ml/hr Goal directed: Standard + SVO2 > 70% using blood trx to Hct > 30 and dobutamine In-hospital mortality 30.5% (Goal directed) vs. 46.5% standard therapy (p=0.009) Over first 72 hours goal directed therapy group had lower lactate levels, higher pH and lower APACHE II scores Rivers et al, NEJM 2001

General Supportive Care Protective ventilatory strategies (low tidal volume ventilation) Electrolytes, glucose Renal dysfunction Nutritional support GI/DVT prophylaxis

Limiting the Sepsis Response Endotoxin blockade Anti-TNF Anti-IL-1 Anti-PAF Corticosteroids Anti-oxidants Coagulation system interference NO interference Hemofiltration

Serum Cytokine Levels in Human Septic Shock 53 episodes of shock evaluated Assessed TNF, IL-1, IL-2, and IL-6 for the first 48 hours No relation between peak levels and mortality Persistence of TNF and IL-6 serum levels predicts a poor outcome in patients with shock Pinsky et al CHEST 103:565-575, 1993

Endotoxin Blockade Initial trials suggested benefit in subgroup with Gram-negative bacteremia (HA-1A, E5) Follow-up trials did not confirm efficacy and possibly a harmful effect

Anti-TNF Antibodies Initial trials suggested efficacy in patients in shock (NORASEPT I) Follow up trial did not confirm (NORASEPT II)

All underwent co-syntropin stim test Effect of Treatment with Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients with Septic Shock 300 patients with septic shock, unresponsive to IVF and low dose pressors as well as organ dysfunction All underwent co-syntropin stim test Hydrocortisone 50 mg iv q 6h and fludrocortisone 50 ug daily or placebos x 7days 28 day survival distribution in patients with relative adrenal insufficiency Annane et al JAMA 288:862-871,2002

229 nonresponders and 70 responders to the cosyntropin Nonresponders: Effect of Treatment with Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients with Septic Shock: Results 229 nonresponders and 70 responders to the cosyntropin Nonresponders: 73 (63%) deaths in placebo group; 60 (53%) deaths in treatment group (p=0.02) Vasopressor therapy withdrawn within 28 days in 46 (40%) in the placebo group and in 65 (57%) in the treatment group (p=0.001) Responders: No significant difference Adverse event rates similar

Corticosteroid Therapy of Septic Shock (CORTICUS) Included all patients in septic shock no matter how they responded to pressors Faster resolution of septic shock in those that received steroids ACTH response did not predict responders No mortality benefit Sprung et al, N Engl J Med 358:111-124, 2008

Steroids in Sepsis: Conclusions Altered HPA axis function common in septic shock Candidates for steroid replacement are those hypotensive (SBP<90) despite 1 hour of pressors Replacement of steroids in such patients is associated with improved survival No routine ACTH tests or steroids in most sepsis patients

Quotables “We in critical care medicine have deep pockets...” Michael J. Apostolakos, circa 1995

“... That’s more than made up for by your superficial thoughts” Quotables “... That’s more than made up for by your superficial thoughts” Paul C. Levy, circa 1995 (now Paul V.C. Levy)

Efficacy and Safety of Recombinant Human Activated Protein C for Severe Sepsis 1690 randomized patients with severe sepsis Drotecogin alfa (activated) vs placebo Both groups received general supportive care Mortality rate 30.8% in placebo group, 24.7% in treatment group at 28 days (p<0.01) Serious bleeding 3.5% treatment group vs 2.0% placebo (p=0.06) Bernard et al NEJM 2001;344:699-709

APC Follow Up Trials ADDRESS: Low disease severity 28-day mortality 18.5% APC vs 17.0% placebo (NS) Severe bleeding 3.9% APC vs 2.2% placebo (p= 0.01) XPRESS: Adjunctive heparin 28-day mortality 28.3% heparin vs 31.9% placebo Severe bleeding 5.2% heparin vs 3.9 % placebo (p=0.16) ENHANCE (open label APC) Mortality 25.3% Severe bleeding 6.5%

Sepsis: Prognosis Severe sepsis carries mortality of 30 - 70% Prognosis influenced by the presence of shock, nature of underlying disease, and the organisms causing sepsis Negative prognostic host factors include immune dysfunction and reduced cardiorespiratory reserve

Sepsis/Multiple Organ Dysfunction Syndrome/Early Goal Directed Therapy: Conclusions Sepsis represents a complex host reaction to severe infection involving coagulation and inflammation MUST remove source of infection(drainage/abx) MUST use early, effective antibiotics Early, aggressive volume resuscitation to predetermined goals is beneficial Corticosteroids in pressor unresponsive septic patients may be associated with reduced mortality Drotrecogin alfa may reduce mortality in patients with severe sepsis (APACHE > 25) Like in MI and CVA, in Sepsis time is tissue! There is a golden treatment period in the first 6 hours…This requires a team effort!